The central noradrenergic system has been localized anatomically using an immunohistochemical method developed for the enzyme dopamine-beta-hydroxylase. The noradrenergic system has been mapped in detail in the entire brain using this method. This study will be extended to include the spinal cord. The immunohistochemical technique will then be combined with the retrograde transport of peroxidase to define the intrinsic organization of the system. The neuroanatomical organization of two additional enzymes catechol-O-methyltransferase and choline acetyltransferase will be localized immunohistochemically. The latter has been purified to homogeneity and the antibodies produced to this enzyme will be used to map the organization of the central cholinergic system especially with regard to determining the source of afferents to the catecholamine system. The anatomical information obtained in the above experiments will be used to formulate hypotheses regarding possible specific functions of these biochemically defined systems. These functions will then be studied using a combination of lesions and various pharmacological agents. Immunohistochemical localization of DBH established a close association of centrally derived DBH-containing axon fibers with the small parenchymal blood vessels of brain. It was hypothesized that the central noradrenergic system has a role in regulating cerebral microcirculation. Recent findings support our hypothesis. A major aim of this proposal is to further characterize this function using lesions and treatment with various pharmacological agents. In order to accomplish this aim a rat model system has been developed and tested that permits the rapid evaluation of drugs for an effect on either blood flow or capillary permeability. The rat system will be used in conjunction with more complex monkey experiments to study this phenomenon. Information obtained by focusing on this relatively non-complex but well-defined and measurable function will serve as a basis for investigation of more complex functions of the central noradrenergic system.